Asporin, an extracellular protein, regulates cardiac remodeling

阿孢菌素是一种细胞外蛋白，调节心脏重塑

• 批准号: 10658863
• 负责人: Sarah J Parker
• 金额: $ 41.75万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658863
• 关键词: Address; Anabolism; Angiotensin II; Autophagocytosis; Binding; Biological; Biology; Blood flow; Cardiac; Cardiac Myocytes; Cell Death; Cell Death Induction; Cell Survival; Cells; Cicatrix; Core Protein; Degenerative polyarthritis; Deposition; Economics; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Extracellular Protein; Fibrillar Collagen; Fibroblasts; Fibrosis; Functional disorder; Genes; Glycosaminoglycans; Glycosphingolipids; Goals; Grant; Health; Heart; Heart Block; Heart Injuries; Heart failure; Hypertrophy; Hypoxia; In Vitro; Infarction; Investigation; Knockout Mice; Leucine; Ligands; Link; Macrophage; Malignant Neoplasms; Mediating; Metabolic; Modification; Morbidity - disease rate; Mus; Myocardial Ischemia; Operative Surgical Procedures; Osteoporosis; Pathologic; Pathway interactions; Patients; Peptides; Play; Process; Proteins; Proteoglycan; Public Health; Pyrimidine; Recombinants; Regulation; Reperfusion Injury; Research; Role; Signal Transduction; Stress; Testing; Therapeutic Intervention; Transforming Growth Factor beta; Treatment Efficacy; asporin; biglycan; cell behavior; cell type; coronary fibrosis; decorin; design; heart function; improved; in vivo; inhibitor; innovation; insight; ischemic injury; metabolic profile; metabolome; mortality; mouse model; novel; novel therapeutic intervention; novel therapeutics; peptide drug; pleiotropism; pressure; prevent; protective effect; public health relevance; purine metabolism; receptor; response; therapeutic evaluation; therapeutic target; therapeutically effective

Project Summary Extracellular matrix (ECM) is critical during cardiac remodeling in altering the cell’s response. Recently, class I small leucine rich proteoglycans (SLRPs) showed enormous impact on the heart’s function during ischemic injury or cardiac remodeling. Adverse cardiac remodeling stimulates fibrotic scar deposition due to increased TGFβ activity on fibroblasts. In the last decade, a non-conventional class I SLRP protein, asporin (ASPN), has been shown to play a role in regulating TGFβ signaling and cell viability in cancer and osteoporosis. The biological impact of ASPN in regulating TGFβ and cell viability in heart is unknown. Our long-term goal is to dissect the detailed mechanisms regulating ASPN activity and its impact on fibroblasts and cardiomyocytes, particularly in the setting of cardiac remodeling. These discoveries will facilitate design of effective ASPN-based therapies for heart failure. The objective of this grant is to characterize the role of ASPN in fibrosis and cardiomyocyte cell viability. Our central hypothesis is that ASPN is released by fibroblasts during cardiac stress and inhibits TGFβ signaling to reduce fibrosis during cardiac remodeling. Further, released ASPN acts on cardiomyocytes to upregulate autophagy and prevent cell death. Our rationale is that identification of the mechanisms to stimulate ASPN-protective effects in cardiac remodeling will offer new therapeutic opportunities. This project will further test therapeutic peptide delivery as well as AAV9-mediated delivery of ASPN gene for efficacy in mitigating reperfusion injury and cardiac remodeling. Our specific aims will test the following hypotheses: (Aim 1) ASPN inhibits fibrosis to maintain cardiac function and prevents adverse cardiac remodeling; (Aim 2) ASPN induces autophagy in cardiomyocytes; (Aim 3) ASPN regulates cardiomyocyte cell death in the setting of ischemia- reperfusion injury. Upon conclusion, we will better understand the role of novel role of ASPN in inhibiting fibrosis and activating autophagy for beneficial cardiac remodeling. This contribution is significant since it will establish the several pathways targeted by ASPN from ECM to fibroblasts and cardiomyocytes. Furthermore, current therapies, while promising in limiting ischemic injury, fail to address the key issue of adverse cardiac remodeling in heart failure patients. The proposed research is innovative as we will investigate the effects of ASPN in regulating fibrosis and cardiomyocyte cell death, an unexamined process to date. Insight into the mechanisms of ASPN activity will pave the way for ASPN-based therapies to benefit cardiac remodeling.

项目概要 细胞外基质 (ECM) 在心脏重塑过程中对于改变细胞的反应至关重要。最近，我班 富含亮氨酸的小蛋白聚糖（SLRP）在缺血性损伤期间对心脏功能产生巨大影响 或心脏重塑。不良心脏重塑会因 TGFβ 增加而刺激纤维化疤痕沉积 对成纤维细胞的活性。在过去的十年中，一种非传统的 I 类 SLRP 蛋白阿孢菌素 (ASPN) 已被研究出来。 研究表明，它在调节癌症和骨质疏松症中的 TGFβ 信号传导和细胞活力方面发挥着作用。生物的 ASPN 对调节 TGFβ 和心脏细胞活力的影响尚不清楚。我们的长期目标是剖析 调节 ASPN 活性的详细机制及其对成纤维细胞和心肌细胞的影响，特别是在 心脏重塑的设置。这些发现将有助于设计有效的基于 ASPN 的疗法 心脏衰竭。该资助的目的是描述 ASPN 在纤维化和心肌细胞中的作用 生存能力。我们的中心假设是 ASPN 在心脏应激期间由成纤维细胞释放并抑制 TGFβ 信号传导以减少心脏重塑过程中的纤维化。此外，释放的 ASPN 作用于心肌细胞 上调自噬并防止细胞死亡。我们的理由是，确定刺激机制 ASPN 对心脏重构的保护作用将提供新的治疗机会。该项目将进一步 测试治疗性肽递送以及 AAV9 介导的 ASPN 基因递送的缓解效果 再灌注损伤和心脏重塑。我们的具体目标将测试以下假设：（目标 1）ASPN 抑制纤维化以维持心脏功能并防止不良心脏重塑； （目标 2）ASPN 诱导 心肌细胞自噬； （目标 3）ASPN 在缺血情况下调节心肌细胞死亡 再灌注损伤。得出结论后，我们将更好地理解 ASPN 在抑制纤维化方面的新作用 激活自噬以促进有益的心脏重塑。这一贡献意义重大，因为它将建立 ASPN 靶向的几种途径（从 ECM 到成纤维细胞和心肌细胞）。此外，当前 治疗虽然有望限制缺血性损伤，但未能解决不良心脏重塑的关键问题 在心力衰竭患者中。拟议的研究具有创新性，因为我们将研究 ASPN 在 调节纤维化和心肌细胞死亡，这是迄今为止未经检验的过程。深入了解机制 ASPN 活性的提高将为基于 ASPN 的治疗有利于心脏重塑铺平道路。